Diagnostic detection chip devices and methods of manufacture and assembly

ABSTRACT

Diagnostic detection chip device designs that reduce cost of fabrication and assembly are described herein. Such chip device designs include features that facilitate use of the chip within a chip carrier device with integrated fluid flow control features and compatibility with conventional sample cartridges and sample processing systems. Associated methods of manufacture and assembly of the chip devices are also provided herein.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.16/713,455, filed Dec. 13, 2019 which claims priority to U.S.Provisional Application No. 62/780,126 filed on Dec. 14, 2018, which isincorporated herein by reference in its entirety.

This application is generally related to U.S. application Ser. No.16/577,650 entitled “System, Device and Methods of Sample ProcessingUsing Semiconductor Detection Chips” filed on Sep. 20, 2019; U.S.application Ser. No. 15/718,840 entitled “Fluidic Bridge Device andSample Processing Methods” filed Sep. 28, 2017; U.S. Pat. No. 6,374,684entitled “Fluid Control and Processing System,” filed Aug. 25, 2000;U.S. Pat. No. 8,048,386 entitled “Fluid Processing and Control,” filedFeb. 25, 2002; and U.S. application Ser. No. 15/217,902 entitled“Thermal Control Device and Methods of Use” filed Jul. 22, 2016; each ofwhich is incorporated herein by reference in its entirety for allpurposes.

BACKGROUND OF THE INVENTION

The present invention relates generally to diagnostic detection chipdevices and methods of manufacture and assembly. In particular, theinvention pertains to semiconductor detection chip devices configuredfor use with a fluid sample transport device and sample processingsystem.

In recent years, there has been considerable development in the use ofsemiconductor detection chips in performing fluid sample analysis (e.g.testing of clinical, biological, or environmental samples). Onecontinual challenge in conventional MEMs technologies in diagnostics hasbeen the lack of flexible sample preparation front end to provide afluid sample suitable for analysis with the semiconductor chips. Samplepreparation of such fluid samples typically involves a series ofprocessing steps, which can include chemical, optical, electrical,mechanical, thermal, or acoustical processing of the fluid samples.Whether incorporated into a bench-top instrument, a portable analyzer, adisposable cartridge, or a combination thereof, such processingtypically involves complex fluidic assemblies and processing algorithms.Developing a robust fluid sample processing system can be extremelychallenging and costly.

Conventional approaches for processing fluid samples typically involvessubstantial manual operation, while more recent approaches have soughtto automate many of the processing steps and can include the use ofsample cartridges that employ a series of regions or chambers eachconfigured for subjecting the fluid sample to a specific processingstep. As the fluid sample flows through the cartridge sequentially fromregion or chamber to a subsequent region or chamber of the cartridge,the fluid sample undergoes the processing steps according to a specificprotocol. Such systems, however, generally include an integrated meansof analysis, and are not typically amenable to use with a semiconductorchip. The standard approach of utilizing semiconductor detection chips,such as “lab on a chip” devices, generally requires a considerablycomplex, time-consuming and costly endeavor, requiring the chip beincorporated into a conventional chip package and then incorporated intomuch larger systems utilizing conventional fluidic transport means totransport a fluid sample to the chip device. The fluid sample istypically prepared by one or more entirely separate systems (oftenincluding manual interaction) and then pipetted into the fluid transportsystem to be supplied to the chip package. These challenges associatedwith pre and post testing processes often minimize the advantages andbenefits of such “lab on a chip” devices and present a practical barrierto their widespread use and acceptance in diagnostic testing. Anotherdrawback or limitation associated conventional approaches of MEMSdiagnostics technology is cost. In order to make high functionalityMEMS/silicon chip technologies feasible in the context of high volumediagnostic testing, the costs of the device should be as low aspossible.

Thus, there is need for approaches that lower the costs of diagnosticchips and improve integration with flowcell components. There is furtherneed for developing chip device that are compatible with existing sampleprocessing technologies to allow for seamless integration with existingsample preparation technologies and to improve efficiency and throughputin fluid sample processing and handling to overcome the challengesdescribed above.

BRIEF SUMMARY OF THE INVENTION

The present invention provides diagnostic detection chips and chipdevices (also referred to as “chip,” “detection chip,” or “semiconductorchip”) that facilitate use of the chip with sample processing devicesand systems that transport processed fluid sample for analysis with thechip. Various approaches are provided that lower the costs ofsemiconductor detection chips and chip devices by improving integrationof the semiconductor chip itself within the overall device. In oneaspect, the device substantially reduces the size of a printed circuitboard (“PCB”) on which the semiconductor chip is provided, for exampleutilizing contacts in an electrical interface that is co-adjacent or ona same side as the active surface of the detection chip. It isappreciated that in some embodiments, the co-adjacent electricalinterface may be configured to be probed from the same side, an oppositeside or any direction desired, and that the co-adjacent electricalinterface may include wire bonds or vias for electrical connection tothe active surface. In some embodiments, this approach allows the PCB tobe replaced with another type of substrate, for example a flexiblesubstrate or laminate. In some embodiments, the electrical interface canbe a flex PCB and utilize flex bonding or TAB (tape automated bonding).In other embodiments, a metal core board can be used as the chipsubstrate where a thermally conductive mount is desired. In still otherembodiments, the substrate can be entirely eliminated and the electricalinterface contact pads can be provided on the chip itself. It isappreciated that such a configuration could utilize probe contacts on asame side as the active surface or could be provided on an oppositeside, for example by through-silicon-vias.

In another aspect, the invention pertains to chip devices compatible foruse with chip carrier devices configured to utilize existing sampleprocessing technologies to perform one or more processing steps, thentransport the processed fluid sample to interface with the semiconductorchip and perform further processing with the chip. Such furtherprocessing typically includes analysis of a target analyte. In someembodiments, the invention further provides means for any of: powering achip device, communicating, programming or signal processing whenperforming testing with a semiconductor detection chip device. In oneaspect, the chip carrier device is configured for use with any of aplurality of differing types of chips and allows for a plug-n-playapproach to utilizing semiconductor detection chips. In someembodiments, the chip carrier device is configured to receive andsecurely engage with a diagnostic chip having an active area, the chipdevice having a flowcell chamber that sealingly engages with the activearea when secured within the chip carrier device.

It is appreciated that the chip device can include any type ofsemiconductor detection chip, including but not limited to CMOS,ion-sensitive FET (ISFET), bulk acoustic, non-bulk acoustic,piezo-acoustic, and pore array sensor chips. In some embodiments, thesemiconductor detection chip serves as a biosensor that combines abiologically sensitive element with a physical or chemical transducer toselectively (and in some embodiments, quantitatively) detect thepresence of specific analytes in a fluid sample. In some embodiments,the chip provides an electrical or optical output signal in response toa physical, chemical, or optical input signal. The system or module usedwith the chip carrier device can include features for powering,communication, signal integration, and data flow when performing testingwith the detection chip and can include software to facilitate use ofthe chip within the system. In some embodiments, to enable additionalnew or enhanced functionality, one or more features that provide sampleprocessing and/or sample preparation capabilities amenable tosilicon-based technologies can be included on the silicon chip. Forexample, the chip could include one or more features for more refinedfluidic manipulation, further refined sample processing, or anycompatible sample processing and/or preparation steps. Such technologiesand functionalities could include but are not limited to:electrophoretic-based separation; fluidic pumping; andelectrowetting-based fluidic manipulation, including droplet generationor pumping, flow sensors, and the like. In some embodiments, the chipcan be bio-functionalized. The chip can utilize bio-functionalizedmaterials (e.g., nanosheets, nanotubes, nanoparticles), for example, assurfaces or coatings. In some embodiments, a surface isbio-functionalized to facilitate controlled movement or immobilizationof a probe or target. It is appreciated that any of these chip featuresdescribed above could be included in any of the embodiments describedherein, and further that the chip carrier can be adapted for use withsuch chip features.

In some embodiments, the chip device is electrically coupled to aplurality of probe contact pads without any backside contacts by PCB viaconnections. This allows for a streamlined chip design in which theprobe contacts are accessible from a same side of the chip as the activearea. In some embodiments, the chip device includes a separateelectrical interface having multiple probe contact pads, the separateelectrical interface disposed adjacent the chip when carried within thechip carrier portion. In some embodiments, the electrical interface canbe a PCB having an area less than the diagnostic chip. Advantageously,the electrical interface can be defined as flex PCB and the probecontacts of the electrical interface are electrically connected tocorresponding contacts of the chip by TAB bonds. In some embodiments,the chip is provided on a support substrate comprising a flex PCB,polymer film or self-adhesive flex laminate. In other embodiments, thechip is defined without any support substrate separate (e.g. rigid PCBunderlying the chip) from a semiconductor wafer in which the chip isdefined. In such embodiments, the chip can include a plurality of probecontacts defined within the chip itself and the chip carrier portion caninclude a window through which the plurality of probe contacts areaccessible when the chip is secured within the chip carrier portion andsealingly engaged with the flowcell chamber. In some embodiments, thechip includes a support substrate of a thermally conductive metal (e.g.copper).

In another aspect, the invention pertains to more cost-effective,streamlined diagnostic chip designs and methods of manufacture andassembly within the chip carrier device with integrated flowcellchamber. Such diagnostic detection chips can include a silicon waferdevice comprising an active area configured for diagnostic detection offluid sample in contact during operation and a plurality of contactsthat are electrically connected to the active area for powering andcommunication with the active area. Advantageously, the plurality ofcontacts can be provided on a same side of the chip as the active area.This allows for a chip that is electrically connected without anybackside via connections, thereby simplifying the chip design andprocess workflow. In some embodiments, the chip comprises a supportstructure of a self-adhesive flex laminate. The contacts can beelectrically connected to a separate PCB having a plurality of probecontact pads on the same side as the active area. In some embodiments,the chip includes a support structure of a thermally conductive metal,such as copper, to facilitate thermal cycling. In other embodiments, thechip is without any support substrate separate from the silicon wafer inwhich the chip is defined. In such embodiments, the plurality ofcontacts can be defined as probe contact pads within the chip itself anddisposed on the same side of the chip as the active area.

In yet another aspect, the invention pertains to a system that includesa sample cartridge configured to hold an unprepared sample, the samplecartridge having multiple processing chambers fluidically interconnectedby a moveable valve body; a module (also referred to as a “cartridgeprocessing module” or “module”) for performing sample preparation, themodule having a cartridge receiver adapted to receive and removablycouple with the sample cartridge and configured to perform samplepreparation; and a diagnostic chip device secured within a chip carrierdevice. The chip carrier device is fluidically coupleable to the samplecartridge via the fluidic interface and electrically coupleable with themodule for powering and communication with a diagnostic detection chipsecured within the chip device. The diagnostic chip device can be inaccordance with any of those described herein.

In still another aspect, the invention pertains to methods offabricating a diagnostic detection chip for use. Such methods caninclude defining a diagnostic chip having an active surface that iselectrically connected to a plurality of electrical contacts accessiblefrom a same side as the active surface. In some embodiments, thediagnostic chip is defined to electrically connect without backsidecontacts having vias through any underlying rigid support substrate(e.g. PCB). This allows for alternative support structures (e.g. flexPCB, laminates, metal or substrates of reduced size and thickness). Insome embodiments, the chip device is configured to electrically connectthe active surface to a plurality of probe contact pads without any wirebonds. In some embodiments, the chip device is designed entirely withoutany separate underlying support substrate (e.g. rigid PCB). In someembodiments, the probe contacts can be formed in the chip itself, eitheralong the same side as the active surface or along the opposite side.Any of the chips described herein can comprise any of CMOS, ISFET, bulkacoustic, non-bulk acoustic, piezo-acoustic and pore array sensor chips.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an overview of a sample cartridge fluidically coupled with achip carrier device and an associated instrument interface board of amodule for receiving and operating the sample cartridge in accordancewith some embodiments of the invention.

FIG. 2A illustrates the instrument interface board of the module, theinstrument interface board having an array of electrical contacts forinterfacing with electrical contact pads of the chip device when thesample cartridge is received within the module, as shown in FIG. 2B, inaccordance with some embodiments.

FIG. 3 illustrates a detailed view of the sample cartridge fluidicallycoupled with a chip carrier device, in accordance with some embodiments.

FIGS. 4A-4E illustrate methods of fabricating, assembling diagnosticchip devices, in accordance with some embodiments.

FIGS. 5A-5D illustrate methods of fabricating, assembling diagnosticchip devices, in accordance with some embodiments.

FIGS. 6A-6C illustrate methods of fabricating, assembling diagnosticchip devices, in accordance with some embodiments.

FIGS. 7A-7C illustrate methods of fabricating, assembling diagnosticchip devices, in accordance with some embodiments.

FIG. 8 illustrates a diagnostic chip device before and instrumentinterface, in accordance with some embodiments.

FIGS. 9A-9C illustrate an integrated diagnostic chip and chip device, inaccordance with some embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to a system, device and methodsfor fluid sample manipulation and analysis, in particular, for transportof a fluid sample from a sample processing device into a chip carrierdevice for analysis using a semiconductor chip.

I. Overview

In one aspect, the invention pertains to an improved or streamlined chipdesign that reduces fabrication costs. In another aspect, the chipdesign improves integration with existing sample processing technologiesby having features compatible with a chip carrier device. Such a chipcarrier device includes fluid control features, such as one or morefluid conduits that are fluidly coupleable with one or more ports of asample cartridge to facilitate transport of a processed fluid samplefrom the cartridge into the chip carrier device through the one or morefluid conduits to facilitate transport of the fluid sample to thesemiconductor chip in the chip carrier device. The sample cartridge isreceived by a module which facilitates operation of the sample cartridgeto perform processing and transport of the processed fluid sample intothe chip carrier device and includes an instrument interface thatelectrically connects to the chip carrier device to facilitate operationof the semiconductor chip carried within the chip carrier device.

A. Chip

As described herein, the term “chip” can refer to the chip itself or achip device that includes the chip and an underlying support substrateand adjacent electrical interface that is electrically connected to thechip. Typically, the chip includes a silicon sensor element having anactive face that is sealingly engaged with a flowcell filled with aprepared fluid sample. In some embodiments, the chip device is designedand configured to be carried within a chip carrier device having anintegrated flowcell and fluid control features so as to be compatiblefor use with a sample processing module as described above. The chipdevice can be bonded within the recess of the chip carrier device or canbe pressed into the recess and secured by a friction fit. The chip isprovided to the user already secured within a chip carrier device, or anend user can assemble the chip within a chip carrier device.

In some embodiments, the semiconductor diagnostic chip is configured toperform sequencing of a nucleic acid target molecule by nanoporesequencing, which detects changes in electrical conductivity and doesnot require optical excitation or detection. The underlying technologiesof such chips can be further understood by referring to U.S. Pat. No.8,986,928. In some embodiments, the semiconductor diagnostic chipanalyzes other attributes of a target molecule in the sample, such asmolecular weight and similar characteristics. Such technologies can befurther understood by referring to: Xiaoyun Ding, et al. Surfaceacoustic wave microfluidics. Lab Chip. 2013 Sep. 21; 13(18): 3626-3649.In some embodiments, the semiconductor diagnostic chip uses surfaceplasmon resonance to provide analysis of a target molecule, for exampleas used in the Biocore™ systems provided by GE Healthcare UK Limited andas described in their Biocore Sensor System Handbook (seegelifesciences.com/biacore). The entire contents of each of the abovereferences are incorporated herein by reference in their entirety.

Typically, the chip is a semiconductor diagnostic detection chip,including but not limited to CMOS, ISFET, bulk acoustic, non-bulkacoustic chips, piezo-acoustic, and pore array sensor chips. Whilesemiconductor diagnostic chips are preferred, it is appreciated that theconcepts described herein are applicable to any type of chip suitablefor use in performing processing or analysis of a fluid sample.

B. Chip Carrier Device

The chip carrier device is adapted to fluidically couple a semiconductorchip to a sample cartridge as described herein. In some embodiments, thechip carrier device includes an electrical interface adapted tointerface with an instrument interface board of a sample processingmodule which operates the sample processing cartridge. It is appreciatedthat the chip carrier device can be configured for use with any type ofchip. In some embodiments, the chip carrier device is designed to allowanalysis of the biological fluid sample with the chip by electricaloperation of the chip by the instrument interface of the module. This isaccomplished through electrical probe contact pads of the chip devicethat are electrically connected to the instrument interface of themodule.

A configuration as described above allows for a more seamless transitionbetween processing of the fluid sample with the sample cartridge andsubsequent processing or analysis of the fluid sample with the chip inthe chip carrier device. This configuration facilitates industrydevelopment of semiconductor chip devices by standardizing processing orpreparation of the sample and delivery of the processed sample to thechip device. Preparation of the sample can be a time consuming andlaborious process to perform by hand and can be challenging to developwithin a next generation chip device. By utilizing a chip carrier deviceinstead of the reaction tube, the user can utilize the sample cartridgeto prepare the sample in a sample cartridge and subsequently transportthe prepared sample into the attached chip carrier device for analysiswith the semiconductor chip device carried therein. Such a configurationexpedites development of semiconductor chip by utilizing existing samplepreparation processes, originally configured for PCR detection, andallowing use of such processes with a chip device.

In some embodiments, the chip carrier device can include one or moreprocessing features in fluid communication with one or more of the fluidflow channels, such as one or more chambers, filters, traps, membranes,ports and windows, to allow additional processing steps during transportof the fluid sample to the second sample processing device. Suchchambers can be configured for use with an amplification chamber toperform nucleic acid amplification, filtration, chromatography,hybridization, incubation, chemical treatment, e.g., bisulfite treatmentand the like. In some embodiments, the chamber allows for accumulationof a substantial portion of the fluid sample, if not the entire fluidsample, for further processing or analysis as needed for a particularprotocol.

C. Sample Cartridge

The sample cartridge can be any device configured to perform one or moreprocess steps relating to preparation and/or analysis of a biologicalfluid sample according to any of the methods described herein. In someembodiments, the sample cartridge is configured to perform at leastsample preparation. The sample cartridge can further be configured toperform additional processes, such as detection of a target nucleic acidin a nucleic acid amplification test (NAAT), e.g., Polymerase ChainReaction (PCR) assay, by use of a reaction tube attached to the samplecartridge. Preparation of a fluid sample generally involves a series ofprocessing steps, which can include chemical, electrical, mechanical,thermal, optical or acoustical processing steps according to a specificprotocol. Such steps can be used to perform various sample preparationfunctions, such as cell capture, cell lysis, binding of analyte, andbinding of unwanted material.

A sample cartridge suitable for use with the invention, includes one ormore transfer ports through which the prepared fluid sample can betransported into a reaction tube for analysis. FIG. 1 illustrates anexemplary sample cartridge 100 suitable for use with a chip carrierdevice 200 in accordance with some embodiments. Conventionally, such asample cartridge is associated with a planar reaction tube adapted foranalysis of a fluid sample processed within the sample cartridge 100.Such a sample cartridge 100 includes various components including a mainhousing having one or more chambers for processing of the fluid sample,which typically include sample preparation before analysis. Inaccordance with its conventional use, after the sample cartridge 100 andreaction tube are assembled and a biological fluid sample is depositedwithin a chamber of the sample cartridge, the cartridge is inserted intoa cartridge processing module configured for sample preparation andanalysis. The cartridge processing module then facilitates theprocessing steps needed to perform sample preparation and the preparedsample is transported through one of a pair of transfer ports into thefluid conduit of the reaction tube 110 attached to the housing of thesample cartridge 100. The prepared biological fluid sample is thentransported into a chamber of the reaction tube 110 through a fluidicinterface of the reaction tube where the biological fluid sample undergonucleic acid amplification and testing to indicate the presence orabsence of a target nucleic acid analyte of interest, e.g., a bacteria,a virus, a pathogen, a toxin, or other target analyte, for example byuse of an excitation and optical detection means. Such a samplecartridge can also be utilized to perform analysis with thesemiconductor chips described herein by use of a chip carrier device,which is fluidically coupleable to the sample cartridge in the same orsimilar manner as a conventional reaction tube.

An exemplary use of a sample cartridge with a planar reaction tubeconfigured for controlled fluid control of a prepared fluid sample isdescribed in commonly assigned U.S. Pat. No. 6,818,185, entitled“Cartridge for Conducting a Chemical Reaction,” filed May 30, 2000, theentire contents of which are incorporated herein by reference for allpurposes. Examples of the sample cartridge and associated module arealso shown and described in U.S. Pat. No. 6,374,684, entitled “FluidControl and Processing System” filed Aug. 25, 2000, and U.S. Pat. No.8,048,386, entitled “Fluid Processing and Control,” filed Feb. 25, 2002,the entire contents of which are incorporated herein by reference intheir entirety for all purposes.

Various aspects of the sample cartridge 100 shown in FIG. 3 can befurther understood by referring to U.S. Pat. No. 6,374,684, whichdescribed certain aspects of the sample cartridge in greater detail.Such sample cartridges can include a fluid control mechanism, such as arotary fluid control valve, that is connected to the chambers of thesample cartridge. Rotation of the rotary fluid control valve permitsfluidic communication between chambers and the valve so as to controlflow of a biological fluid sample deposited in the cartridge intodifferent chambers in which various reagents can be provided accordingto a particular protocol as needed to prepare the biological fluidsample for analysis. To operate the rotary valve, the cartridgeprocessing module comprises a motor such as a stepper motor that istypically coupled to a drive train that engages with a feature of thevalve in the sample cartridge to control movement of the valve andresulting movement of the fluid sample according to the desired samplepreparation protocol. Fluid metering and distribution functions of therotary valve can be utilized and controlled to perform a particularsample preparation protocol.

It is appreciated that the sample cartridge described above is but oneexample of a sample processing device suitable for use with the chipcarrier devices in accordance with embodiments described herein. Whilechip carrier configurations that allow for use of such a samplecartridge are particularly advantageous as they allow utilization ofexisting sample cartridges and sample processing devices, it isappreciated that the concepts described herein in regard to the chipdesign can be applied to other sample processing devices, for example,the dual piston rotary valve device described in U.S. Pat. No.7,032,605, incorporated herein by reference. It is further appreciatedthat the chip designs described herein can be configured to becompatible with various other chip carrier devices, sample cartridgeconfigurations or other fluid sample processing devices and components,for example, any of those described in U.S. Provisional Application No.62/734,079 filed Sep. 20, 2018, incorporated herein by reference.

D. Instrument Interface

In another aspect, the module includes an instrument interface tofacilitate powering and communication with the chip. The instrumentinterface can include a circuit board adapted to engage an electricalinterface of the chip device to allow the module to electrically power,control and communicate with the chip device. In some embodiments, theinstrument interface is located within a common housing of the module toprovide more seamless processing between the sample cartridge and thechip device. The instrument interface can be controlled by the module incoordination with transport of the fluid sample from the samplecartridge to the chip.

In some embodiments, the instrument interface board includes probecontacts and is mechanically mounted on a pivot that moves toward thechip carrier device when received within the module. The instrumentinterface board is configured to pivot from an open position before thesample cartridge is loaded to an engaged position when loaded. A cam(not shown) positions the interface board so that the probes contact theelectrical interface of the chip device. The probe contacts aretypically pogo pins on the instrument interface board that contactcorresponding probe contact pads on the electrical interface of the chipdevice to allow the module to control analysis of the fluid sample withthe chip.

The instrument interface board can also host passive and activeelectronic components in addition to those of the chip carrier as neededfor various other tasks. For example, such components could include anycomponents needed for signal integrity, amplification, multiplexing orother such tasks.

E. Example Systems

FIG. 1 illustrates an overview of a system utilizing a conventionalsample cartridge 100 fluidically coupled with a chip carrier device 200.The sample cartridge 100 is adapted for insertion into a bay of a sampleprocessing module configured to perform one or more processing steps ona fluid sample contained within the sample cartridge throughmanipulation of the sample cartridge. An instrument interface 300 of themodule is incorporated into the module within the bay in which samplecartridge 100 is received and includes a plate 301 having a receptacleopening 302 through which the chip carrier device 200 extends whencartridge 100 is positioned within the bay. The instrument interface 300further includes an instrument board 310, such as a PCB board, thatextends alongside a major planar surface of chip carrier device 200 andincludes electrical contacts 312 arranged so as to electrically couplewith corresponding probe contact pads on the major planar surface of thechip device.

FIG. 2A illustrates the instrument interface board 310 of the module andthe electrical contacts 312 for interfacing with electrical contact padsof the chip device. Typically, the contacts 312 are arranged in apattern, such as a rectangular array, that corresponds to the contactsof the chip device. In this embodiment, the contacts 312 are configuredas pogo-pins so as to deflect upon insertion of the chip carrier device200 through receptacle opening 302 to provide secure electrical couplingbetween probe contacts 312 and corresponding probe contact pads on theinstrument interface of the chip device secured within the chip carrierdevice 200, as shown in FIG. 2B. Although a rectangular array ofpogo-pins is depicted here, it is appreciated that the electricalcontacts could be arranged in various other patterns, in accordance witha corresponding chip carrier device and that various other contactconstructions could be realized. In some embodiments, the electricalcontacts could be configured as one or more edge connectors or othertypes of multi-pin connector arrangements. It is further appreciatedthat the instrument interface need not utilize every contact so as to becompatible for use with a chip carrier device having differing numbersor arrangements of contact pads, as desired. In some embodiments, theelectrical contacts could include an additional adapter so as to besuitable for use with various differing types of chip carrier devices.In some embodiments, it may be cost effective to package a semiconductorcontroller as an adjunct to the chip carrier device such that the signalconnectivity is minimized. Such an approach could use any suitableconnector means, which can include a standard connector type, such as aUSB interface (e.g. [+1,−2, sig 3, sig 4]).

FIG. 3 illustrates a detailed view of the sample cartridge 100fluidically coupled with chip carrier device 200 with integrated fluidflow control, in accordance with some embodiments. Typically, the chipcarrier device 200 is a planar device that includes a flowcell chamberfor engaging against the active area of the chip and a fluidic interface201 that fluidically couples to a fluid sample container, such as samplecartridge 100. In this embodiment, the fluidic interface 201 fluidicallycouples to the sample cartridge 100 and includes a pair of fluid ports(not visible) that couple with corresponding fluid ports of the samplecartridge. On one side of the planar device is the flowcell chamber, forexample, as shown in FIG. 9A. The other side of the planar device caninclude one or more fluid control features, such as an amplificationchamber. The chip carrier device can be formed from a suitably rigidmaterial such that the chip carrier device 200 extends outward from thesample cartridge 100, which allows clearance for various othercomponents, such as the instrument interface board of the module and/orthermal cycling units.

The chip carrier device 200 includes a fluidic interface 201 that can beconfigured with fluid ports (e.g. Luer type ports) and flangearrangement that is the same or similar as that of a typical PCRreaction tube so that the fluid sample adapter can easily interface withexisting sample cartridges, as described previously. It is appreciatedhowever that various other types of fluid ports (e.g. Luer type ports,pressure fit, friction fit, snap-fit, click-fit, screw-type connectors,etc.) in various other arrangements could be used. Typically, thefluidic pathways are defined in a first substrate and sealed by a secondsubstrate, such as a thin film, similar to the construction ofconventional PCR reaction tubes. In some embodiments, the fluid sampleadapter also features alignment and assembly bosses as well asmechanical snaps so that a chip carrier component or chip can be securedagainst a flowcell of the flowcell portion with ease. In someembodiments, the chip carrier device includes one or more channels thatextend between fluid-tight couplings without any chambers, valves orports between the proximal and distal ends. In other embodiments, thedevice includes one or more valves, or ports. In some embodiments, theone or more channels can include one or more chambers or regions, whichcan be used to process or analyze the fluidic sample, for example,chambers or regions for thermal amplification of a nucleic acid target,filtration of the sample, chromatographic separation of the sample,hybridization, and/or incubation of the sample with one or more assayreagents.

As can be seen in the example of FIG. 9A, the fluidic path leads to aflowcell chamber 953 through set of flowcell ports 953 a, 953 b withinthe flowcell. In this embodiment, the flowcell chamber 953 includes aninlet flowcell port 953 a and outlet flowcell port 953 b, which allowfor controlled fluid transport through the fluid sample adapter 951 intothe flowcell chamber 953 via the fluidic inlet 951 a and fluidic outlet951 b. Typically, the flowcell inlet 953 a is disposed below theflowcell outlet 953 b when the fluid sample adapter 201 is orientedvertically to facilitate controlled fluid flow through the flowcellchamber 953. It should be understood that use of the terms “inlet” and“outlet” do not limit function of any fluid inlets or outlets describedherein. Fluid can be introduced and evacuated from both or either. It isappreciated that the chip carrier device can be formed as an integralcomponent or assembled from multiple components, and can incorporatevarious other features (e.g. valve, filter).

In some embodiments, the chip carrier device (or at least a partialassembly) is provided pre-attached to a sample cartridge with thefluid-tight couplings coupled with corresponding fluid ports of thecartridge. For example, a sample cartridge may be provided alreadycoupled with the fluid sample adapter 201 such that an end-user caninsert any chip within the chip carrier device 200 against the flowcellchamber to facilitate sample detection with a chip.

The flowcell portion of the chip carrier device is configured with anopen chamber that, when interfaced with an active area of a chip withinthe chip carrier, forms an enclosed flowcell chamber to facilitateanalysis of the fluid sample with the chip. The flowcell is shaped andconfigured to fluidly couple with a chip within a chip carrier attachedto the fluid sample adapter 201. Typically, the fluidic pathway of thefluid flow portion fluidically connects to the flowcell chamber throughfluid ports located at the top and bottom of the flowcell chamber. Thechamber is formed by raised lands or ridges that come in contact withthe active silicon or glass element used in the detection scheme. Theactive element is located on the chip carried within the chip carrierand secured to the flowcell by bonding and sealing, which can beaccompished by various means (e.g. using epoxy preforms, dispensed epoxyor other adhesives, a gasket, a gasket with adhesive, mechanicalfeatures, or various other means). The purpose of the flowcell adapteris to create a complete flowcell chamber, bounded by the detectionsurface on one side and the flowcell adpater on the remaining sides. Theflowcell can include one or more coupling features defined as alignmentand assembly bosses as well as mechanical snaps that are received incorresponding holes to faciliate alignment of the chip when securedwithin.

The chip carrier device can include a contoured region dimensioned toreceive the chip within. The contoured region includes a raised ridgealong the perimeter thereof to engage a corresponding portion of theflowcell portion and effectively seal the chip within the chip carrierdevice. The raised lands or ridge around the open flowcell chamberengage an active surface of the chip so as to form an enclosed flowcellchamber. The chip carrier can include a window to provide access to theplurality of probe contacts defined on the chip itself or on anelectrical interface of the chip device. Alternatively, the chip carrierdevice can be dimensioned so that the electrical interface of the chipor chip device extend beyond the distal end of the chip carrier deviceso as to be accessible by the instrument interface of the module.

It is appreciated that the chip carrier device with integrated fluidcontrol can include any of the feature or structures described herein,or any of those described in U.S. Provisional Application No. 62/734,079filed Sep. 20, 2018.

II. Diagnostic Chip Devices and Assemblies

In one aspect, integrated diagnostic chip designs are described thatfurther simplifies the fundamental design of the chip device, therebyreducing manufacturing costs and allowing for further integration andsimplification of the chip device.

Embodiments previously described in U.S. Provisional Application No.62/734,079 assume use of a chip design fabricated according toconventional techniques. The current low cost state of the art is to usechip on board (COB) strategies to eliminate separate semiconductorpackaging elements. Generally, COB techniques rely on a PCB substrate towhich the chip is mounted and perform wire bonding operations andsubsequent bond protection operations on the device. The PCB serves thepurpose of creating a mounting surface for the chip and utilizes vias onthe PCB to electrically connect the chip to connection points (e.g.probe contact pads) disposed on the side opposite the chip. Thisapproach allows a large number of contact pads to be distributed overthe relatively large surface area on the opposite side of the chip. Useof a separate PCB in this manner aids the semiconductor processingworkflow and is the widely accepted, most common approach. Onesignificant drawback with this approach is that it is fairly expensive,requiring additional materials within the PCB (often costing as much asthe chip itself) and incurs further expenses within the workflow stepsneeded to clean and mount the chip on the PCB. Therefore, the inventiondescribed herein provides alternative, integrated approaches todesigning and fabricating a diagnostic chip to facilitate use within achip carrier device and take advantage of existing sample preparationtechniques while further reducing the fabrication and workflow costs ofthe chip. These approaches are advantageous over conventional COBtechniques and allow for the further simplification without anymodification or only slight modification in chip design.

There are several different approaches proposed for streamliningdiagnostic chip design for use with the sample processing systems andmethods described herein. These approaches include: (i) utilizing probecontacts on a separate PCB adjacent the chip, which allows foradditional alternative approaches including: (ii) given the reducedsize/thickness requirements of any PCB or support substrate of thediagnostic chip, replacing the PCB with a less expensive supportsubstrate (e.g. thinner, lighter, more flexible, etc.) (iii) utilizingflex PCB and tab bonding techniques; (iv) using a metal core board tosupport the chip as a thermally conductive mount; (v) eliminating thesubstrate entirely and forming probe contact pads in the chip itself.These different approaches are described in further detail in FIGS.23A-26C below.

A. Probe Contacts on Separate PCB

In a first aspect, the streamlined chip design entails substantiallyreducing the size of the PCB and moving the PCB alongside of the chipdevice (e.g. semiconductor/MEMs) and performing the wire bonding/wirebonding protection in the areas of co-adjacency of the components. Inthis approach, the diagnostic chip is designed to electrically connectwith probe contacts provided on a separate PCB board. This allows thePCB board or substrate of the chip to be reduced in size and furtherallows the probe contacts to be probed from the same side as the chip.In some embodiments, this approach mounts both the PCB and device onto aseparate surface, typically during the same pick and place operation ofthe semiconductor packaging work flow. This allows the mountingsubstrate to be very inexpensive, such as plastics and composites, andalso opens the possibility of using thermally conductive metals orceramics as the supporting substrate. This strategy generally prefersthat the connections to the completed device be made from the same sideas the devices. In some embodiments, this concept could be used andconfigured such that the probe contacts still face in the oppositedirection. The main cost reduction is the size of the PCBs and theflexibility given to the process by allowing different PCBs and chipdevices to be matched without significant redesigns. FIGS. 4A-4Eillustrates sequential steps of assembling a chip device assembly 400utilizing a chip having associated probe contact pads provided on aseparate PCB, as described above.

FIG. 4A shows a support substrate 401, which can be smaller and thinnerthan would be customarily used if the probe contacts on a backside ofthe PCB by via connections. FIG. 4B illustrates a diagnostic chip 410that is die cut and mounted on the substrate 400 with an active area 411facing upwards and having an array of electrical contacts 412. In someexisting chip designs, this array of contacts is considerably smallerthan probe contact pads and are used for testing purposes during chipmanufacturing. Adjacent the chip 410 is a PCB 420, having an areasmaller than the chip area and having probe contact pads disposed on thesame side as the chip. FIG. 4C shows the electrical contact arrayconnected to the probe contacts 422 of PCB 420 by wire bonds 430. FIG.4D shows the addition of bond protection 2140 (e.g. layer of epoxy).FIG. 4E shows the assembly secured within chip device 450 having anintegrated flowcell engaged with active area 411. As can be seen, theprobe contact pads 422 remain accessible to be probed by an electricalinterface within a sample processing module in which the device 450 isinserted, as described in previous embodiments.

B. Alternative Chip Substrates/Connection Types

Given that the probe contact pads are provided on a separate PCB, thesupport substrate of the chip can not only be smaller and thinner, butcan utilize various different materials that are less expensive and/orhave additional mechanical properties that provide further advantages.For example, the substrate can be a flexible material, such as a flexlaminate, which are more economical. Further, the reduced area allowsthe substrate to be more easily mounted, for example, a self-adhesiveflex laminate feature can be used as the adhesive provides sufficientbond strength for a smaller lighter flex laminate (as compare to aconventional PCB component).

FIGS. 5A-5B shows assembly of another chip device assembly 500. In thisexample, the assembly includes a streamlined chip 510 and flex PCB 530mounted to a substrate 500. The probe contacts are electricallyconnected to the chip 510 by wire bonds 520 over which bond protection540 is added.

In another aspect, the PCB on which probe contacts are provided can alsobe flex PCB. This lends itself to less expensive bonding methods such asTAB bonding techniques, which are generally cheaper and faster than wirebonding at very high volume production.

FIGS. 5C-5D show such an example chip device assembly 500′ that includesa streamlined chip 510 and flex PCB 530 mounted to a substrate 500, withthe probe contacts electrically connected to the chip 510 contacts byTAB bonding 522 over which bond protection 540 is added.

C. On-Chip Probe Electrical Contacts/Connections

In yet another aspect, an integrated, streamlined chip can be designedthat uses probe contact pads defined in the chip itself. This approachutilizes an additional portion of the chip (on a same side as the activearea) such that wire bonded connections through a PCB are avoided. Thisdesign avoids the necessity of a separate PCB component for the probecontacts and further avoids any bonding procedures and various workflowsteps. In some embodiments, the chip can be manufactured on analternative support substrate, such as any of those described herein.Advantageously, the chip can be manufactured without any separatesupport substrate, for example, the silicon wafer in which the chip isdefined can act as the support. In such embodiments, a step of thinningthe silicon wafer is unnecessary, thereby providing a more costeffective and streamlined fabrication as compared to conventionallypackaged chip devices. In such embodiments, any available wafers can beused, for example wafers having a thickness of 925, 775, 725, 675, 625,or 525 um (thicknesses typically corresponding to wafer diameter). It isappreciated however that any suitable thickness wafer could be used.

This approach allows for an even more cost effective approach ofeliminating the separate PCB entirely and thus any electrical bondingrequirements to the chip. By putting the onus of making the electricalconnections to the chip onto the instrument entirely, the need for aseparate PCB, PCB Flex component, and wire or TAB bonds and protectioncan be completely eliminated. This allows for a design where the chip(e.g. bare silicon/MEMS device) can be mounted directly into an integralflowcell/chip carrier device. The elimination of the steps pertaining tothe separate PCB and associated electrical connections save time andcost on the order of the cost of the chip itself. Typically, thisapproach prefers that the chip (e.g. silicon/MEMS device) has areasonably low number of connections such that a sufficient area on thedevice can be allotted to the connections. This approach may incur someadditional cost in regard to the additional area of silicon utilized forthe contact connections, but for most chip designs, this increase incost is significantly offset by the savings in the elimination of theseparate PCB and associated reduction in workflow.

FIGS. 6A-6C show the assembly of an example chip device assembly 600 inaccordance with the above approach. FIG. 6A shows the streamlined chip610 having an active area 610 and a probe contact array 620 formed alongone side of the same side. In this embodiment, chip 610 includes 12 padsingle row contacts, although it is appreciated that fewer or morecontact pads could be included. FIG. 6B shows assembly of the chip 610within a chip carrier device 650 having an integrated flowcell. FIG. 6Cshows chip 610 securely engaged within the chip carrier device 650 suchthat the active area is sealingly engaged with the integrated flowcell(not shown). As can be seen in FIG. 6C, the chip device 650 includes awindow 652 through which the contact pad array 620 can be accessed byprobes of an electrical interface of a module in which the chip device650 is inserted. In this embodiment, the contact pads are fairly small(e.g. 12 pads at 0.8 mm pitch). Such a design would require ratherprecise and small instrument connection interface design to ensure theprobes consistently and reliably engaged the corresponding contact pads.

FIGS. 7A-7C show a substantially similar chip assembly 700, however, thechip 710 includes an integral probe contact array 740 defined in a dualrow pad arrangement that sacrifices some additional area of the chipdevice to allow for sufficiently large number of pads, with each padhaving sufficient area to make the instrument design significantlyeasier. In this embodiment, the spacing between the pads and arrangementof the pads allow use of a commonly available electrical contactarrangement (e.g. a 1.27 mm pitch, dual row, 16 pin pogo header). It isappreciated that the probe contact pads could be designed according toany dimension desired taking into account the available chip area. As inthe previous embodiment, the chip 710 is secured within a chip carrierdevice 750 having a fluidic interface 751 and a window 752 through whichthe probe contact array 740 is accessible.

FIG. 8A shows a chip carrier device 850, in accordance with thosedescribed in FIGS. 6A-7C, before insertion into an instrument interface860 of the module that includes a header 865 with probes (not visible)that engage corresponding on-chip contact pads exposed through window852. The use and operation of the instrument interface with the chip isgenerally in accordance with the concepts discussed in the embodimentsin FIGS. 1-3 and 8 .

FIG. 9A-9C show detail views of a chip device assembly 900, inaccordance with those described in FIGS. 6A-6C. FIG. 9A shows the chipcarrier device 950 having an integrated flowcell chamber 953 in fluidcommunication with fluidic interface 951. The flowcell chamber isdisposed within a recessed portion dimensioned to fittingly receive thechip 910 within so as to sealingly engage an active area of the chipagainst the flowcell chamber. The device can include a separate gasketto facilitate sealing or the gasket can be a raised portion definedwithin the device itself. In some embodiments, the chip carrier device950 is formed as a unitary component and can be formed by injectionmolding or any suitable means. In other embodiments, the chip carrierdevice can be assembled by multiple components, for example, as in thepreviously described embodiments. The flowcell is filled with preparedfluid sample through flowcell inlet/outlet ports 953 a, 953 b in fluidcommunication with the inlet/outlet ports 951 a, 951 b of the fluidicinterface 951.

As can be seen in the top view of FIG. 9B, the size and dimensions ofthe chip 951 corresponds to the recess in the chip carrier device 950.The chip carrier device 950 can include various retention or couplingfeatures to secure chip 951 within, for example, retention tab 955 andsnap-fit couplings 954 that are dimensioned and arranged to resilientlyreceive the chip and secure the chip with the active area sealinglyengaged against the flowcell chamber. As can be seen in the undersideview of FIG. 10 , the integrated flowcell/chip carrier device 950includes a flowcell inlet channel 930 a in fluid communication withfluidic inlet 951 a of fluidic interface 951 and a flowcell outletchannel 950 b in fluid communication with 951 b such that the samplecartridge and module to which the device is attached precisely controlsthe flow of fluid sample from the fluid sample cartridge into theflowcell chamber through the fluidic interface. The chip 910 includes anintegrated probe contact pad array 920 on the chip surface on a sameside as the active area 911, the array being positioned to be accessiblethrough the probe contact window 952 of the integrated flowcell/chipcarrier device 950.

In the foregoing specification, the invention is described withreference to specific embodiments thereof, but those skilled in the artwill recognize that the invention is not limited thereto. Variousfeatures, embodiments and aspects of the above-described invention canbe used individually or jointly. Further, the invention can be utilizedin any number of environments and applications beyond those describedherein without departing from the broader spirit and scope of thespecification. The specification and drawings are, accordingly, to beregarded as illustrative rather than restrictive. It will be recognizedthat the terms “comprising,” “including,” and “having,” as used herein,are specifically intended to be read as open-ended terms of art.

1-29. (canceled)
 30. A method of fabricating a diagnostic detection chipdevice for use within a diagnostic chip device assembly, the methodcomprising: defining a diagnostic chip having an active surface on oneside; and electrically connecting the active surface to a plurality ofprobe contact pads on an electrical interface so as to be accessiblefrom the same side as the active surface.
 31. The method of claim 30,wherein the chip comprises any of CMOS, ISFET, bulk acoustic, non-bulkacoustic, piezo-acoustic and pore array sensor chips.
 32. The method ofclaim 30, further comprising: coupling the chip to a support substratecomprising any of: a flex PCB, a flexible laminate, a ceramic and ametal.
 33. The method of claim 30, wherein the chip device is definedaccording to any of claims 1 through
 13. 34. The method of claim 30,wherein the probe contact pads are electrically connected to a pluralityof electrical contacts defined on the chip along the same side as theactive area.
 35. The method of claim 30, wherein electrically connectingcomprises wire bonding or TAB bonding.
 36. The method of claim 30,wherein the chip is without any rigid support substrate separate from asilicon wafer in which the chip is defined.
 37. The method of claim 30,wherein the plurality of probe contact pads are defined within the chipitself.
 38. The method of claim 37, wherein the probe contact pads aredefined along the same side of the chip as the active surface.
 39. Themethod of claim 37, wherein the probe contact pads are arranged withinone or more rows along or near one edge of the chip.
 40. The method ofclaim 30, further comprising: securing the diagnostic chip within adiagnostic chip carrier so as to sealingly engage the active face of thechip within a flowcell chamber of the chip carrier.
 41. The method ofclaim 40, wherein the diagnostic chip is positioned such that the probecontacts pads are accessible through a window of the chip carrier. 42.The method of claim 30, further comprising: securing the diagnostic chipto a thermally conductive metal substrate.
 43. The method of claim 42,wherein the thermally conductive metal substrate is copper.
 44. Themethod of claim 30, wherein the diagnostic chip is defined to beoperable without requiring any via connections through any rigid PCBsupport substrate underlying substantially the entire chip.
 45. A methodof fabricating a diagnostic detection chip device for use within adiagnostic chip device, the method comprising: fabricating a diagnosticchip having an active surface on one side; and electrically connectingthe active surface to a plurality of probe contacts of an electricalinterface, wherein the electrical interface is: defined on a co-adjacentPCB or defined within the chip itself.